Melanoma is a cancer of melanocytes, pigmented skin cells. This cancer is the most common cause of death due to a skin cancer, and is clinically characterized by skin lesions that are asymmetric, have irregular borders, and have variegated color. It is estimated that in 2015, over 73,000 new cases of melanoma will be diagnosed and nearly 10,000 deaths will occur from this disease. Fortunately, melanoma is highly treatable by surgical resection if diagnosed at an early stage, but chances of survival decline rapidly if the disease progresses with metastases. Melanoma that has metastasized distantly causes 5-year survival of patients to fall drastically from 98% to 16%. One major subset of patients with melanoma (~50%) carry a driving amino acid substitution mutation in the BRAF gene, V600E. This mutated melanoma is highly responsive to targeted chemotherapy but unfortunately, nearly all patients recur after treatment with fatal disease. To address this clinical challenge, we propose to investigate the ability of systemic viroimmunotherapy developed by our laboratory to effectively treat metastatic melanoma. This therapy utilizes the Vesicular Stomatitis Virus (VSV) expressing tumor- associated antigens to act as an immunological vaccine - priming the immune system to attack tumors. We have demonstrated the ability of this VSV targeting endogenous tumor antigens to control disease in mice when combined with the clinically relevant agents: immune checkpoint inhibitors and stereotactic radiation therapy. Now, we hypothesize that we can improve upon our established treatment strategy by completing these specific aims: (1) Generate a new VSV that expresses the simultaneously safety-enhancing and immune-stimulating cytokine interferon-? (IFN-?) (2) Using a mouse model of BRAF mutant melanoma, add VSV immunotherapy to the current clinical standard of care for this subset of metastatic melanoma: targeted BRAF inhibitors, immune checkpoint inhibitors (anti-PD-1 antibody), and stereotactic radiation therapy. Completing these aims will be crucial to achieving the overarching goal of this research: to generate the pre- clinical data necessary to test this promising VSV immunotherapy in human clinical trials.